tbuckley/cabot-search huggingface dataset:
MiR-198 sensitizes pancreatic cancer to gemcitabine treatment through downregulation of VCP-mediated autophagy maturation.
Authors: Christian Marín-Müller, Dali Li, Jian-Ming Lu, Zhengdong Liang, Osvaldo Vega-Martínez, William Fisher, Changyi Chen, Qizhi Cathy Yao
Journal: Journal of Clinical Oncology (2022)

e16290 Background: The mechanism of human pancreatic ductal adenocarcinoma (PDAC) resistance to nucleoside analog and first-line chemotherapy drug gemcitabine is not clearly understood, but some studies have associated it with increased autophagy. In cancer biology, autophagy plays dual roles as it can promote tumor suppression during early stages, but in established tumors, it plays a crucial role in tumor growth by enhancing survival under metabolic and therapeutic stress. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of a network of tumorigenic factors, including the Valosin-containing protein (VCP), which has been reported to play an important role in autophagy. In this study, we investigate whether the repression of VCP through miR-198 replacement disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment. Methods: MIAPaCa2 cells with forced overexpression of mesothelin (MSLN) and AsPC-1 cell lines and, CDX and PDX mouse models were used for gemcitabine sensitization studies. For miR-198 replacement, a miR-198 expression vector-loaded lactic co-glycolic-acid-modified polyethylenimine polyplex (LPNP-p198) was used. Autophagy disruption experiments were run over miR-198 and/or VCP overexpressing cell lines. Nude mice were used for subcutaneous and orthotopic CDX models and SCID/Beige were used for the subcutaneous PDX model. Results: Cell lines were treated with LPNP-p198 in combination with gemcitabine and cell growth was significantly inhibited when compared to gemcitabine alone. Additionally, it was determined that miR-198 disrupts the autophagy maturation process and, that it is then restored by overexpression of VCP. LPNP-p198 can effectively enter tumor cells and induce tumor sensitization in vivo, resulting in an 80-90% reduction of tumor burden and metastatic spread in the LPNP-p198 plus gemcitabine group when compared to controls, with the concomitant downregulation of VCP expression in the tumor tissue. In addition, this group had the fewest mice with jaundice, ascites, and metastases to the abdominal cavity, spleen, liver, and kidney. Finally, to address the potential of the observed effect in the context of the heterogenic nature of PDAC, we confirmed our findings in a PDX mouse model, where a marked reduction in tumor burden was observed in the LPNP-p198 plus gemcitabine group compared to controls. Conclusions: Our findings indicate that miR-198 replacement disrupts the autophagy maturation process and sensitizes PDAC cells to gemcitabine through VCP repression, indicating a potential therapeutic strategy for targeting gemcitabine-resistant PDAC and, establishing the use of LPNPs as a prototype for effective nucleic acid delivery in vitro and in vivo, with potential to be used from bench to clinic.
60w superpulse thulium fiber laser for RIRS in large volume stones (&gt;1000 mm3) – a prospective study on efficacy and outcomes
Authors: G. Soundarya, V. Chandramohan, P. Ramakrishna, S. Siddalinga, A. Hemnath, B. Manas, P. Rakesh
Journal: European Urology (2022)
A study of AK104 (an anti-PD1 and anti-CTLA4 bispecific antibody) combined with standard therapy for the first-line treatment of persistent, recurrent, or metastatic cervical cancer (R/M CC).
Authors: Jing Wang, Hanmei Lou, Hong-Bing Cai, Xin Huang, Guiling Li, Li Wang, Ting Liu, Wei Liu, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2022)

106 Background: Current first-line standard therapy (SOC) for R/M CC is platinum-based chemotherapy +/- bevacizumab (bev). AK104 monotherapy has shown promising efficacy and tolerable toxicity in pretreated R/M CC (NCT04380805). In this study, we report the efficacy and safety of AK104 combined with SOC for the first-line treatment of R/M CC (NCT04868708). Methods: The multicenter, open-label, phase II study enrolled R/M CC pts without previous systemic therapy. Eligible pathological types were squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma. Pts were assigned to 3 cohorts (A-15/A-10: AK104 15/10 mg/kg + PTX 175mg/m 2 + DDP 50 mg/m 2 /CBP AUC 5, q3w; B-10: AK104 10 mg/kg + PTX 175 mg/m 2 + DDP 50 mg/m 2 /CBP AUC 5 + bev 15 mg/kg, q3w). All pts received AK104 until PD or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included ORR, PFS per RECIST1.1, and OS, etc. Results: 45 pts were enrolled at 6 centers from Jun 3, 2021, to Nov 5, 2021. As of Jan 10, 2022, we assessed safety in all pts and efficacy in pts with at least one tumor assessment result. TRAEs of any grade occurred in 43 (95.6%) pts. Grade ≥3 TRAEs occurred in 23 (51.1%) pts. The most common TRAEs were anemia (55.6%), white blood cell count decreased (46.7%), rash (24.4%), and hypoesthesia (24.4%). The most common grade ≥ 3 TRAEs were anemia (15.6%), white blood cell count decreased (11.1%), neutrophil count decreased (8.9%), and platelet count decreased (8.9%). TRSAE occurred in 17 (37.8%) pts. IrAEs of any grade, assessed by INV, occurred in 24 (53.3%) pts. Grade ≥ 3 irAE occurred in 8 (17.8%) pts. One death due to hemorrhagic shock occurred in cohort B-10 and was judged as treatment-related. ORR were 73.3% (11/15) for A-15, 68.8% (11/16) for A-10, 92.3% (12/13) for B-10, respectively. The response to the treatment was favorable regardless of CPS (Table). PFS or OS data are not mature by cut-off date. Conclusions: AK104 combined with standard therapy was well tolerated, with encouraging antitumor activity in pts with R/M CC. Meanwhile, long-term safety evaluation still needs following up. A phase III trial is ongoing to evaluate the efficacy of AK104 plus standard therapy in first-line treatment for R/M CC (NCT04982237). Clinical trial information: NCT04868708. [Table: see text]
The landscape of STK11 mutations and hotspots in Chinese patients with solid tumors.
Authors: Yun Han, Junyan Su
Journal: Journal of Clinical Oncology (2022)

e15112 Background: STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due to loss of AMPK regulation of mTOR and HIF-1-α. STK11 has been identified as a tumor suppressor in several types of cancers. Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer. However, the genomic features of STK11 are obscured in Chinese solid tumors. In this study, we investigated the landscape of STK11 in Chinese patients with solid tumors. Methods: Next-generation targeted sequencing of major cancer-related 599 genes in a large cohort of 5420 Chinese solid tumors. Results: STK11 mutations were identified in 184 (3.39%, 184/5420) Chinese solid tumors patients. Although STK11 mutations are negligible in solid tumors, endometrial cancer patients (15.79%), esophagus and esophagogastric junction cancer (9.09%), ovarian cancer (4.92%), and lung cancer (4.92%) possess relatively high rates of STK11 mutation. However, STK11 alterations were not found in head and neck cancer, kidney cancer, and CNS tumor cases. A total of 194 mutation sites have been identified in STK11, including 43 pathogenic/ likely pathogenic mutations, the most prominent mutational hotspots are P281fs, D194Y, W308C, S216F, D53fs, and Y60, occupying almost 48.84% of all mutations in STK11. A total of 17 patients harbored copy number variations (CNV) of STK11 in Chinese solid tumors, mainly occurring in the neuroendocrine tumor, breast cancer, and gastric cancer. Conclusions: We found a unique genomic feature of STK11 in Chinese solid tumor patients. Our results show that STK11 may be a potential therapeutic target.
GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
Authors: Timothy Francis Cloughesy, Brian Michael Alexander, Donald A. Berry, Howard Colman, John Frederick de Groot, Benjamin M. Ellingson, Gary B. Gordon, Mustafa Khasraw, Andrew B. Lassman, Eudocia Quant Lee, Michael Lim, Ingo K. Mellinghoff, Apoorva Nelli, James R. Perry, Erik P. Sulman, Kirk Tanner, Michael Weller, Patrick Y. Wen, W. K. Alfred Yung
Journal: Journal of Clinical Oncology (2022)

TPS2078 Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. GBM AGILE has screened over 1000 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. While enrollment had an initial dip during the early stages of the pandemic (April-May, 2020), with flexible processes including remote based monitoring, minimizing in person visits, and remote provision of IMP, the enrollment rebounded by June, 2020. Through the use of improved and efficient processes allowed within a master protocol/adaptive platform trial infrastructure, GBM AGILE has been seamlessly operating a global trial during a global pandemic. Clinical trial information: NCT03970447.
COVID-19 vaccine immunogenicity among chronic liver disease patients and liver transplant recipients: A meta-analysis
Authors: Ka Shing Cheung, Chiu Hang Mok, Xianhua Mao, Ruiqi Zhang, Ivan FN Hung, Wai Kay Seto, Man Fung Yuen
Journal: Clinical and Molecular Hepatology (2022)

Data of coronavirus disease 2019 (COVID-19) vaccine immunogenicity among chronic liver disease (CLD) and liver transplant (LT) patients are conflicting. We performed meta-analysis to examine vaccine immunogenicity regarding etiology, cirrhosis status, vaccine platform and type of antibody.We collected data via three databases from inception to February 16, 2022, and reported pooled seroconversion rate, T cell response and safety data after two vaccine doses.Twenty-eight (CLD only: 5; LT only: 18; both: 2; LT with third dose: 3) observational studies of 3,945 patients were included. For CLD patients, seroconversion rate ranged between 84% (95% confidence interval [CI], 76-90%) and 91% (95% CI, 83-95%), based predominantly on neutralizing antibody and anti-spike antibody, respectively. Seroconversion rate was 81% (95% CI, 76-86%) in chronic hepatitis B, 96% (95% CI, 93-97%) in non-alcoholic fatty liver disease, 85% (95% CI, 75-91%) in cirrhosis and 85% (95% CI, 78-90%) in non-cirrhosis, 86% (95% CI, 78-92%) for inactivated vaccine and 89% (95% CI, 71-96%) for mRNA vaccine. The pooled seroconversion rate of anti-spike antibody was 66% (95% CI, 55-75%) after two doses of mRNA vaccines and 88% (95% CI, 58-98%) after third dose among LT recipients. T cell response rate was 65% (95% CI, 30-89%). Prevalence of adverse events was 27% (95% CI, 18-38%) and 63% (95% CI, 39-82%) among CLD and LT groups, respectively.CLD patients had good humoral response to COVID-19 vaccine, while LT recipients had lower response.
The impacts of remote learning in secondary education during the pandemic in Brazil
Authors: Guilherme Lichand, Carlos Alberto Doria, Onicio Leal-Neto, João Paulo Cossi Fernandes
Journal: Nature Human Behaviour (2022)

Abstract The transition to remote learning in the context of coronavirus disease 2019 (COVID-19) might have led to dramatic setbacks in education. Taking advantage of the fact that São Paulo State featured in-person classes for most of the first school quarter of 2020 but not thereafter, we estimate the effects of remote learning in secondary education using a differences-in-differences strategy that contrasts variation in students’ outcomes across different school quarters, before and during the pandemic. We also estimate intention-to-treat effects of reopening schools in the pandemic through a triple-differences strategy, contrasting changes in educational outcomes across municipalities and grades that resumed in-person classes or not over the last school quarter in 2020. We find that, under remote learning, dropout risk increased by 365% while test scores decreased by 0.32 s.d., as if students had only learned 27.5% of the in-person equivalent. Partially resuming in-person classes increased test scores by 20% relative to the control group.
Non-invasive detection of esophageal carcinoma by integrative analysis of low-pass whole methylome sequencing of plasma cell-free DNA.
Authors: Dan Liu, Bin Jiang, Weizhi Chen, Peiyao Nie, Hongyu Xie, Tiancheng Han, Shunli Yang, Yu S. Huang, Fang Lv, Shuying He, Ying Yang, Yulong LI, Yuanyuan Hong, Jianing Yu
Journal: Journal of Clinical Oncology (2022)

4067 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect esophageal carcinoma. Methods: Plasma cfDNA sampels from 85 patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 60 cancer patients and 398 healthy individuals and the independent testing cohort includes 25 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =96.25% in the discovery cohort and AUC =91.15% in the independent testing cohort. Under a specificity of 95.29% (CI: 87.64% - 100.00%), sensitivity was 72.00% (CI: 56.00% - 92.00%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect esophageal carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
First line avelumab in PD-L1+ve metastatic or locally advanced Urothelial Cancer (aUC) patients unfit for cisplatin: The ARIES trial
Authors: R. Iacovelli, C. Ciccarese, M. Brunelli, N. Battelli, C. Buttigliero, C. Caserta, S. Buti, D. Santini, E. Naglieri, L. Galli, E. Verri, P. Ermacora, M. Milella, C. Masini, G. Aprile, L. Milesi, F. Spina, M. Rizzo, I. Sperduti, G. Fornarini, G. Tortora
Journal: European Urology (2022)
How to promote the sharing of RWS data in China's second-tier cities?
Authors: Shasha Wang, Fang Wang, Zhen Zeng, Fang Gao, Haifeng Qin
Journal: Journal of Clinical Oncology (2022)

e18719 Background: Real world studies(RWS) measure the actual effects of treatment, not the efficacy in trials, making conclusions from real world studies more extrapolative. Clinical SCI papers are primarily based on the exploration of real-world clinical practice. We investigated the status of SCI papers published by 500 front-line clinicians, hoping to find some effective ways to promote the sharing of clinical research results in the real world. Methods: From December 2021 to January 2022, 500 front-line clinicians in 26 cities completed a 20-question online survey. Results: All of respondents were attending physicians in second-tier cities, and 7% of respondents were Bachelors, 61.8% were Masters and 31.2% were Doctors. The survey indicated surprising 83.1% of the respondents had no experience in SCI paper publication. Those(56.0%) had trouble getting paper published. Among all the respondents, 29.6% did not know the grade and submission requirements of SCI journals, 27.1% have no idea how to operate it, 24.9% had insufficient knowledge of medical statistics, 7.8% were not clear about the research design requirements for papers submitted to SCI journals. The major reasons(88.2%) for the above situation was no opportunity to receive professional systematic training. In terms of expecting help, 63.2% of patients expected to receive systematic lectures from the SCI editorial board，and 25.1% expected their peers to share their experiences in turning RWS data to paper. Conclusions: The survey indicated the ability improvement of paper publication was helpful to promote the sharing of clinical research results in the real world, and further benefit more patients.
Treatment De-Intensification for Patients With HPV-Positive Head and Neck Cancers
Authors: Maura L. Gillison
Journal: Journal of the National Comprehensive Cancer Network (2022)

Cisplatin and 70 Gy of intensity-modulated radiotherapy remain the standard of care (SoC) in HPV-positive head and neck cancer, with no data to support de-escalation as a new SoC. Cetuximab compromises locoregional tumor control and overall survival without reduced toxicity, although with different toxicity. Eliminating cisplatin and reducing radiation by 10 Gy compromise progression-free survival but not overall survival, and replacement of SoC adjuvant chemoradiotherapy with low-dose radiotherapy plus docetaxel compromises progression-free survival for patients with extracapsular extension and/or multiple cervical metastases, without significantly reducing grade 3 toxicities. The current trend toward numerous, single-institution phase II trials should be minimized, because they can be difficult to interpret. Instead, to move the field forward with more definitive outcomes, focus should be placed on taking promising concepts to multicenter, randomized phase II/III studies with clear statistical endpoints.
The modified glasgow prognostic score (MGPS) and the mortality prediction MODEL II (MPM II) CAN predict mortality in patients with breast cancer admitted to intensive care: A retrospective cohort study.
Authors: Omer Fatih Olmez, Burcu Tunay, Ahmet Bilici, Ayberk Bayramgil, Güneş Dorukhan Çavuşoğlu, Huseyin Oz
Journal: Journal of Clinical Oncology (2022)

e13055 Background: We aimed to examine whether inflammatory markers and various risk scoring systems could be utilized to predict the prognosis of breast cancer patients hospitalized in the intensive care unit. Methods: In this retrospective cohort study, we evaluated 71 breast cancer patients followed and treated by the Medical Oncology Department of Medipol University Faculty of Medicine who were admitted to the intensive care unit at any stage of their treatment between 2014 and 2020. In addition to scoring systems developed to assess prognosis in the ICU, we recorded and calculated various inflammation-related markers. All data were compared between groups formed according to survival status. Results: The median age was 58 (range: 33-90) years. Thirty-seven (52.1%) patients had died and 34 (47.9%) patients had survived. Neutrophil lymphocyte ratio (p = 0.021), Modified Glasgow prognostic score (p &lt; 0.001), APACHE II score (p &lt; 0.001) and MPM II (admission) (p &lt; 0.001) were significantly higher in the exitus group than in the survivors. Lymphocyte monocyte ratio (p = 0.030) and prognostic nutritional index (p = 0.004) were significantly higher in the discharged group than in the exitus group. When we evaluated performance of the prognostic scores to predict mortality, we found APACHE II score (AUC: 0.939, 95% CI: 0.888 - 0.990), MPM II-Admission (AUC: 0.936, 95% CI 0.880 - 0.992) and mGPS (AUC: 0.727, 95% CI: 0.600 - 0.854) had the highest area under curve values. Multivariable regression revealed that longer chemotherapy duration (≥2 weeks), having an mGPS score of 2 points, and high MPM-II (≥36 points) were independently associated with mortality. Conclusions: Among the inflammatory markers and scores examined, mGPS and MPM-II were found to be independently associated with mortality in breast cancer patients hospitalized in the intensive care unit. In addition, patients with longer chemotherapy duration had a higher risk of mortality, but this result was limited by various possible confounders.
Optimizing timing and indications for 68Ga-PSMA PET/CT in patients with biochemical recurrent prostate cancer after radical prostatectomy
Authors: D. Robesti, E. Mazzone, G. Gandaglia, A. Stabile, S. Scuderi, F. Barletta, L. Nocera, R. Leni, L. Marandino, D. Raggi, A. Necchi, E. Balestrazzi, S. Fanti, A. Farolfi, L. Bianchi, R. Schiavina, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Comparison of retzius-sparing versus standard approach robotic assisted laparoscopic prostatectomy for localized prostate cancer: A systematic review and meta-analysis from KSER update series
Authors: D.Y. Chung, H.D. Jung, M.H. Lee, D.K. Kim, S.W. Lee, S. Paick, S.H. Jeon, J.Y. Lee
Journal: European Urology (2022)